This invention relates to thalidomide prodrugs, to a method of producing them, and to the use of the same as a pharmaceutical active ingredient.
The excessive formation of the cytokinin TNF-xcex1 (tumour necrosis factor xcex1) plays a central part in the pathogenesis of graft-versus-host syndrome, of multiple sclerosis, of transplant rejection, aphthous stomatitis, erythema nodosum leprosum, morbus Boeck, rheumatoid arthritis and a series of other diseases which are associated with inflammatory symptoms. One basis for the therapy of these diseases consists of the targeted suppression of the release of TNF-xcex1, by administering inmmunomodulating active ingredients, such as dexamethasone, pentoxifylline or thalidomide for example.
In the treatment of aphthous stomatitis, thalidomide has proved to be superior to classical immunosuppressants. Other examples of diseases in which thalidomide has exhibited good efficacy without resulting in a general imnmunosuppression include cutaneous lupus erythematosus, pyoderma gangrenosum and orogenital ulcers with morbus Behcet, as well as ulcerations in HIV-infected patients, which do not differ histologically from aphthous ulcers and in whichxe2x80x94in contrast to the majority of HIV-associated mucocutaneous lesionsxe2x80x94no microbial instigators can be detected. As distinct from stomatitis aphthosa, these lesions, which can be characterised as major aphthae, occur in the entire digestive tract, and when located in the pharyngeal space or the oesophagus make the absorption of food difficult, and also make the taking of oral medication difficult, due to the pain which they cause. The pathogenetic factors are endogenous mediators which have effects on the endothelium and on circulating leukocytes. Under the influence of locally-formed TNF-xcex1 and other cytokinins, there is a marked increase in the adhesiveness of the endothelium in relation to leukocytes, which makes a definitive contribution to the development of venous vasculitis. Substances which, like thalidomide, suppress this alteration of the endothelium without at the same time blocking the specific cellular immune defence, can constitute an important advance in therapy.
In severe cases of pharyngeal or oesophageal ulcers, in which the taking of oral medication is made difficult, or in which this may even be impossible, and in cases of HIV-associated pathology in which severe symptoms of diarrhoea make the use of oral medication unpredictable, the parental administration of active ingredients is appropriate. However, the low solubility of thalidomide in water (0.012 mg/ml; Arch. Pharm. 321, 371 (1988)) constitutes an obstacle to the parenteral application of this active ingredient.
Thalidomide derivatives are known from DE 42 11 812 which comprise a benzoyloxymethyl group with an amine-bearing substituent on the nitrogen atom of the glutarimide residue. These thalidomide derivatives have a considerably higher solubility in water than that of thalidomide The pH values of aqueous solutions of these compounds are considerably lower than the physiological pH range, however, so that it is necessary to increase the pH before their application. In the course of this procedure, the corresponding bases are precipitated, with the consequence that the advantage of higher solubility in water is eliminated to a considerable extent or even completely.
The underlying object of the present invention was to develop thalidomide prodrugs which are water-soluble within the physiological pH range. The object was also that the compounds to be developed should not give rise to any toxicological effects due to the separation of non-physiological prodrug residues.
It has been found that the requirements imposed on the compounds to be developed are fulfilled by selected thalidomide prodrugs.
Accordingly, the present invention relates to thalidomide prodrugs of formula I 
wherein R denotes xe2x80x94CHR1xe2x80x94NHR2 or xe2x80x94(CH2)nCOOH, R1 denotes H or C1-4 alkyl, R2 denotes H, C1-3 alkyl, C(O)xe2x80x94CH2xe2x80x94NHR3 or an amino-protective group, R3 denotes H or an amino-protective group, and n is an integer between 2 and 4, in the form of their bases or salts of physiological acids.
The definition of the R1 wherein R1 is a C1-4 alkyl radical includes both straight chain and branched hydrocarbon radicals, which may be substituted with OH, COOH, xe2x80x94C(O)NH2, NH2, xe2x80x94NHC(O)NH2, xe2x80x94NHC(NH)NH2 or Sxe2x80x94C1-3xe2x80x94-alkyl, or with a substituted or unsubstituted phenyl group.
The definition of R2 wherein R2 is a C1-3 alkyl radical includes straight chain and branched hydrocarbon radicals.
Compounds which are suitable as thalidomide prodrugs of formula I, wherein R denotes xe2x80x94CHR1xe2x80x94NHR2, are those in which the R1 radical denotes H, CH3, xe2x80x94CH(CH3)2, xe2x80x94CH2CH(CH3)2 or xe2x80x94CH(CH3)CH2CH3, particularly those compounds in which the R1 radicals denote H, CH3 or xe2x80x94CH(CH3)2 and R2 denotes H, CH3, C(O)xe2x80x94OC(CH3)3 or C(O)xe2x80x94Oxe2x80x94CH2xe2x80x94C6H5.
Of the thalidomide prodrugs of formula I in which R denotes xe2x80x94(CH2)nCOOH, the compound in which n is 2 is particularly suitable.
The present invention further relates to a method of producing thalidomide prodrugs of formula I, wherein R denotes xe2x80x94CHR1xe2x80x94NHR2, R1 denotes H or C1-4 alkyl, R2 denotes H, C1-3 alkyl, C(O)xe2x80x94CH2xe2x80x94NHR3 or an amino-protective group, R3 denotes H or an amino-protective group, and R3 denotes H or an amino-protective group, which is characterised in that N-hydroxymethylthalidomide is reacted with an amino acid, the amino function of which is protected, in the presence of a carbodiimide or carbonyldiimidazole, and the protective group for the amino function is subsequently split off by acidolysis if desired.
The t-butyloxycarbonyl radical and the benzyloxycarbonyl radical are particularly suitable as a protective group for the amino function. The reaction of N-hydroxymethylthalidomide with a protected amino acid is conducted in the presence of equimolar to double equimolar amounts of a carbodiimide, for example dicyclohexylcarbodiimide, or of a carbonyldiimidazole, in an organic solvent, for example dichloromethane, chloroform, acetone, dimethylformamide and/or pyridine. The reactions can be conducted in the presence of a catalyst, for example 4-pyrrolidinopyridine or 4-dimethylaminopyridine.
Acidolytic cleavage of the amino-protective group is preferably effected with trifluoroacetic acid, optionally in the presence of an organic solvent, for example dichloromethane.
The present invention also relates to a method of producing thalidomide prodrugs of formula I wherein R denotes xe2x80x94(CH2)nCOOH, which is characterised in that N-hydroxymethylthalidomide is reacted with an acid anhydride in the presence of an amine.
Succinic anhydride is preferably used as the acid anhydride. Triethylamine and/or pyridine are suitable as the amines which are usually used in equimolar to double equimolar amounts with respect to N-hydroxymethylthalidomide. The reactions are usually conducted in an organic solvent, for example dichloromethane, chloroform, pyridine and/or dimethylformamide, in the presence of a catalyst, for example 4-pyrrolidinopyridine or 4-dimethylamino-pyridine.
Salts of compounds according to the invention with physiologically compatible acids, for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and aspartic acid, are obtainable either from the corresponding bases or from trifluoroacetates. For the production of hydrochlorides, the corresponding trifluoroacetates are preferably converted into hydrochlorides with the aid of a weakly basic anion exchanger. Short chain aliphatic alcohols, for example methanol, are preferred as solvents.
The compounds according to the invention can be applied as substances which are soluble in water in the physiological pH range between 70 and 75, and are toxicologically harmless. Accordingly, the present invention also relates to the use of a thalidomide prodrug of formula I as an active ingredient in drugs, which are preferably administered parenterally.
In addition to at least one thalidomide prodrug of formula I, drugs according to the invention contain support materials, fillers, solvents, diluents, colorants and/or binders. The selection of these adjuvant substances and of the amounts to be used depends on whether the drug is to be administered intravenously, intraperitoneally, intradermally, intramuscularly, intranasally or locally.
The amount of active ingredient to be administered to the patient, which depends on the weight of the patient, on the type of parenteral application, on the indication and on the degree of severity of the illness, is usually between 0.1 and 10 mg/kg of a thalidomide prodrug of formula I.
Due to their pronounced immunomodulatory action, which does not result in a general immunosuppression, thalidomide prodrugs of formula I are suitable for the treatment of all diseases which are characterised by a high level of TNF-xcex1 formation or by focal vasculides.